Extrusion Process for High Active Pharmaceutical Ingredient Loading That Exhibit Controlled Release: Formulations and Evaluation Thereof

 

Shaik Parveen Begum1, R.K. Mohamed Mutahar1,2, B.M. Dinesh3, C.S.R. Lakshmi1 and L.V.G. Nargund1

1Dept. of Pharmaceutics, Nargund College of Pharmacy, Bangalore, Karnataka, India.

2Research Scholar, Dept. of Pharmaceutics, Karpagam University, Coimbatore, Tamil Nadu, India.

3Dept. of Pharmaceutics, K.L.E.S. College of Pharmacy, Bangalore, Karnataka, India.

*Corresponding Author E-mail: parveen.sweetga@gmail.com

 

ABSTRACT:

Drugs required in a large dose size are difficult to design into a matrix based controlled release drug delivery system (CRDDS) because of the requirement of high amounts of polymers or other matrix formers, along with general excipients. In order to overcome this limitation, preparation of matrix based CRDDS containing high dose of active pharmaceutical ingredient (API) using extrusion as a process were formulated and evaluated which forms the backbone of the present research. Tablets extruded directly from the calibrated modified tablets extruder die exhibited extended release properties, excellent content uniformity; exceptional tablet hardness and friability results over control samples produced via direct compression and showed compliance with pharmacopoeial standards. The in vitro drug release data justifies the release process is diffusion-controlled as all the formulations best fitted into first order release kinetics and Higuchi’s equation. To confirm diffusion mechanism results, the data were fit into Korsmeyer- Peppas model, which revealed anomalous transport kinetics. The accelerated stability studies of optimized formulations TEM.2 made it clear that only negligible amount of drug content degraded. Release pattern was almost unaffected and could be claimed to be stable at the end of six months. It can be concluded that, apart from direct compression method of preparation of controlled release matrix tablets of nicotinic acid, extrusion process can also be successfully used as an effective method for the preparation tablets requiring high dose of API.

 

KEYWORDS: Extrusion, Matrix tablets, Nicotinic acid, Stability studies.

 

 


INTRODUCTION:

Preparing formulations that contain high API loading and exhibit controlled API release via conventional pharmaceutical processing technology has proven to be difficult. As the amount of API increases, the quantity of dissolution rate controlling additives and other excipients must be reduced. This often has a negative impact on dosage form preparation processes and/or results in dosage forms with poor mechanical properties. The conventional solution is to increase the dosage size, but there is a practical limit to this approach. Extrusion is a process originating from the plastic industry and has recently found its place in the array of pharmaceutical manufacturing operations. It is a process of converting raw material into a product of uniform shape and density by forcing it through a die under controlled conditions.

 

In the present research work the extrusion process was carried out using Nargund laboratory extruder (NLE), keeping in view the making of tablets for laboratory scale. NLE ‘the one and only one of its kind’ has been designed and engineered on 09/09/09 in laboratory, P.G. Dept. of Pharmaceutics, Nargund College of Pharmacy, Bangalore. Nicotinic acid (NA) to be claimed as an antidyslipidemic drug should be dosed for not less than 1g to 3g/day is a sufficient example for high API loading. Hence NA has been taken as a model drug in the present research. The MTs composed of NA and the release retarding material (polymer), offers the simplest approach in designing an extended-release system. As is well established a Hydrophilic polymer i.e. Hydroxypropyl Methylcellulose (HPMC) and Hydrophobic polymer i.e. Ethyl Cellulose (EC) are polymeric excipients best suited to produce MTs using extrusion process.

 

Materials and Methods:

Nicotinic acid (NA) the model drug for this study has been procured from Western India, Pvt Ltd, Rajasthan, India. HPMC (E4M) and EC (20 cps) from S.D. Fine Chemicals, Mumbai, India.  Polyvinylpyrrolidone (PVP-K30), Magnesium stearate and Talc from Loba chemie, Pvt Ltd, Mumbai. India. All the other ingredients used throughout the study are of analytical grade.

 

Designed of Nargund Laboratory Extruder (NLE):

NLE ‘the one and only one of its kind’ has been designed and engineered on 09/09/09 in laboratory, P.G. Dept. of Pharmaceutics, Nargund College of Pharmacy, Bangalore; for the purpose of making both granules and tablets for Laboratory scale. There are other benefits to using E/S over traditional processing techniques. These include fewer unit operations, better content uniformity, an anhydrous process, a dispersion mechanism for poorly soluble drugs, a low energy alternative to high shear granulation, and less processing time compared to conventional wet granulation.19 As shown in Fig 1, names of the different parts of the NLE are   1) Cylindrical Steel Barrel 2) Sieve Screen 3). Handle 4) Barrel cap 5) Steel conveyer 6) Shaft 7) Rod die (Standard Calibrated pipe) 8) Sharp stainless steel blade 9) Stand with metal clamps.

 

Figure 1: Different parts of Nargund Laboratory Extruder.

 

Description of the different parts of the NLE: Barrel: Cylindrical steel Barrel (Fig 2A) measuring 6inches in length and 57.85mm in diameter fixed firmly to the stand with clamps. The position of the barrel may be kept either horizontal or vertical, one end of the barrel is open to accommodate the barrel cap, and the other end is for rod die.

Conveyer: A steel conveyer (Fig 2B) with handle at one end and the shaft on the other; barrel cap is in the middle.

 

Figure 2: A. Cylindrical Steel Barrel.

B. Steel Conveyer.

Tablet Extruder Die: Rod die (Standard calibrated pipe) (Fig 3A) with six equal intersections of 5.14mm thickness and 14.23mm inner diameter giving 6 tablets in one batch as shown in (Fig 3B) and (Fig 3C) respectively.

 

Figure 3: Tablet Extruder Rod die.

 

Granules Extruder Die: Sieve screen of 57.84mm in diameter with a sieve size of approximately 1.5mm for Granules by spheronization.

 

Sharp Blade: sharp stainless steel blade of the required thickness is used to run between intersections of the rod pipe to cut the coherent mass into uniform size tablets.

 

Methods:

Preparation of MTs of NA:  MTs of NA have been prepared by three methods. Each method utilizes1:1ratio of NA and mixed polymers (HPMC E4M and EC (20 cps), 4:1, 3:1, and 3:2) as shown in (Table 1).

 

Tablet extrusion (TE) method: Step I: The CM was placed in the CB and forced out through the rod die (Fig 3A) giving continuous rod like shaped CM. Now a sharp blade is run between each intersection of the rod die to give tablets (Fig 1) of uniform size and shape (5.14mm in Thickness and 14.23mm in Diameter). Step II: These Tablets were immediately dried in a hot air oven at 500 for 24 hrs.

 

Direct compression (DC) method:  For the purpose of comparison the identical formulations evolved as a result of the TE method and DC method (Table 1). Here the tablets are prepared by compressing the sieved and weighed ingredients in a 10-station rotary tablet compression machine (Rimek Mini Press-1, Ahmadabad, India), equipped with concave punches of 12.5mm diameter. Nine die cavities were blocked with stainless steel solid blocks.

 

Results and Discussion:

Effect of Pre- compression parameters: As shown in (Table.2), the granules of different formulations were evaluated for Db, Dt, PC, HR and angle of repose. As such all the results obtained indicate that the formulated granules match the compressibility and flow properties satisfactorily.

 

Table 1: Composition of Matrix Tablets of Nicotinic Acid.

Ingredients

Formulations

Tablet extrusion

Method

Direct compression

method

TEM.1

TEM.2

TEM.3

DCM.1

DCM.2

DCM.3

NA (mg/tab)

250

250

250

250

250

250

HPMC-E4M (%)

80%

75%

60%

80%

75%

60%

EC (20 cps) (%)

20%

25%

40%

20%

25%

40%

PVP- K30 (%)

0.01%

0.01%

0.01%

Mag stearate  (%)

1%

1%

1%

Talc (%)

1%

1%

1%

 

 

Effect of Post- compression parameters: As shown in (Table.2), All prepared formulations showed uniform thickness, diameter, drug content indicating a uniform contents in the formulations. The prepared tablets were superior in hardness accompanied with very negligible amount in percentage weight loss.

 

Effect of hardness: The hardness effect of MTs of NA prepared by DC and TE method on the release rate was evaluated and the results of TE method compared with the DC method. Usually an increase in hardness of a tablet is accompanied by a decrease in release rate, due to a decrease in porosity of the tablet. A comparison of the hardness values of the tablets is shown in (Fig 4), which depicts that the formulations prepared by TE method are having higher hardness value (Table 2). The final comparison revealed that the MTs of NA prepared by TE method were superior in hardness accompanied with very negligible amount in percentage weight loss (Friability).

 

Figure 4: Comparison of the Hardness of tablets prepared by DC and TE method.

 

Effect of In vitro release rates: The release rate of NA prepared by DC and TE method formulations using mixed polymers.No significant differences in release rates were observed in prepared formulations, as shown in Fig.5. The difference in the method of preparation and polymer combination ratios (4:1 and 3:1).

 

Figure5: Release profiles of prepared formulations.

 

Drug release kinetics: The dissolution data of all formulations when fitted in accordance with the first-order equation showed good linearity ranging from (R2: 0.922 to 0.988) (Table 3). All the formulations in this investigation could be best expressed by Higuchi’s equation, as the plots showed high linearity (R2: 0.933 to 0.977) (Table 3). All the formulations showed exponent “n” value that ranged from 0.88 to 0.95 (Table 3). The diffusional exponent; “n” between 0.5 and 1.0 which indicate the anomalous transport kinetics (non-Fickian diffusion kinetics) that means the drug is released by the combined mechanism of pure diffusion controlled and swelling controlled drug release.

 

Stability studies: The tablets of optimized formulations TEM.2 were subjected to accelerated stability studies for 6 months as per ICH guidelines. The parameters like color, % drug content, % drug release and difference factor (ƒ1) and similarity factor 2) were evaluated (Table 4). The studies made it clear that only negligible amount of drug content degraded, release pattern was almost unaffected and could be claimed to be stable at the end of six months. The f1 and f2 analysis of TEM.2 (Fig.6) showed a superimposable dissolution profile before and after the period of six months storage.

 

Figure 6: Comparative release profiles of optimized formulation TEM.2 before and after storage.

 


Table 2: Evaluation of Pre and Post Compression Parameters of formulations.

Pre compression parameters

Post compression parameters

FORMULATIONS

Bulk density

(gm/ml )

 

Tapped density

(gm/ml )

Compressibility

Index(% )

Hausners ratio

Angle of

Repose ( 0 )

Thickness (mm)

Diameter (mm)

Average Weight (mg)

Hardness  (Kg/cm2 )

Friability (%)

Drug content

(%)

% Drug Release

±S.d

(n=10)

±S.d

(n=10)

±S.d

(n=01)

±S.d

(n=01)

±S.d

(n=03)

±S.d

(n=03)

±S.d

(n=03)

±S.d

(n=20)

±S.d

(n=10)

±S.d

(n=03)

±S.d

(n=03)

±S.d

(n=06)

DCM.1

0.49± 0.0012

0.56

±0.1021

12.5± 0.1201

1.14

±0.111

36.73

±0.001o

4.59

±0.002

12.49

±0.003

508.1

±0.111

4.9

±0.001

1.2

±0.131

100.6

±0.121

99.6± 0.111

DCM.2

0.32± 0.0213

0.39

±0.1112

17.95± 0.1003

1.22

±0.022

38.6

±1.032o

4.55

±0.021

12.48

±0.133

503.3

±0.112

4.2

±0.021

1.6

±0.013

96.3

±0.102

96.1±0.032

DCM.3

0.22± 1.0023

0.28

±1.0201

21.43± 0.1001

1.3

±0.201

38.33

±0.102o

4.58

±1.022

12.48

±1.232

507.2

±1.001

4.6

±0.002

1.7

±0.123

99.4

±0.002

96.9±0.012

TEM.1

NA

NA

NA

NA

NA

5.12

±0.013

14.22

±0.122

503.1

±0.032

10.8

±0.013

0.0

 

97

±0.021

96.2±0.041

TEM.2

NA

NA

NA

NA

NA

5.13

±0.131

14.22

±0.012

505.4

±0.013

10.3

±0.122

0.0

 

98.2± 0.1001

97.7±0.012

TEM.3

NA

NA

NA

NA

NA

5.13

±0.122

14.21

±0.01

507.2

±0.112

10.6

±0.002

0.1

±0.211

96.3

±0.021

96± 0.021

 

Table 3:  Mathematical model Fitting of Prepared formulation.

Formulations

Zero order

First order

Higuchi model

Korsmeyer- Peppas

Intercept

Slope

K0,

(%hr-1)

 

Intercept

Slope

Kr ,

(%hr-1)

 

Intercept

Slope

KH,

(%hr-1)

 

Intercept

“n”

Value

 

Release mechanism

TEM.1

0.85

7.526

22.62

22.62

0.948

-0.186

2.128

2.128

0.974

30.33

0.255

0.255

0.585

1.188

0.92

AT

TEM.2

0.85

3.63

26.05

26.05

0.922

-0.084

2.087

2.087

0.977

20.89

3.369

3.369

0.647

0.909

0.92

AT

TEM.3

0.828

3.571

27.44

27.44

0.951

-0.093

2.091

2.091

0.968

20.73

4.645

4.645

0.636

0.902

0.93

AT

DCM.1

0.797

3.951

27.26

27.26

0.985

-0.092

2.050

2.050

0.942

23.08

1.651

1.651

0.688

0.970

0.88

AT

DCM.2

0.763

4.922

29.61

29.61

0.972

-0.164

2.126

2.126

0.933

25.08

5.286

5.286

0.601

1.015

0.95

AT

DCM.3

0.846

3.598

25.88

25.88

0.988

-0.061

1.988

1.988

0.975

20.74

3.313

3.313

0.649

0.910

0.91

AT

*AT = Anomalous Transport.

 

Table 4:  Evaluation of optimized formulations at accelerated stability studies.

Optimized Formulations TEM.2

Evaluating Parameters (n = 03)

Condition

Sampling period

Color

Drug content (%)

Drug release

(%)

f1 and  f2 analysis before and after storage

f1

f2

40 ° ± 2 ° / 75 % RH ± 5% RH

0  Month

White

98.2 ±0.101

97.7 ±0.012

10.8

86.9

1st Month

White

98.2 ±0.021

97.7 ±0.101

 

2nd  Month

White

98.2 ±0.103

97.7 ±0.013

3rd  Month

White

98.2 ±0.021

97.7 ±0.022

4th  Month

White

97.6 ±0.111

96.1 ±0.03

5th  Month

Pale yellow

97.4 ±0.001

95.9 ±0.014

6th Month

Pale yellow

97.0 ±0.012

95.5 ±0.022

11.3

86.1

 

 


CONCLUSION:

The method developed by the extrusion process is simple and cheap and they do not need additional equipment and procedures for the industrial applications. Further, extrapolating the ideal formulation to commercial scale is also easily feasible by performing sufficient scaling up studies.

 

 

References:

1.       Rauwendaal. Ch. et al. Polymer Extrusion. Munchen: Hanser publishers,1986; 20-25.

2.       Coppens K, et al. Hypromellose, Ethylcellu-lose, and Polyethylene Oxide Use in Hot Melt Extrusion – A Review Article. Pharmaceutical Technology. January 2006.

3.       Ghebre-Sellassie I, Martin C. Pharmaceutical Extrusion Technology. New York: Marcel Dekker INC; 2003.

4.       Carstensen JT. Solid state stability. In: Carstensen JT, Rhodes CT, editors. Drug stability: Principles and practices. New York: Marcel Dekker INC,2000;145-89.

 

 

 

 

 

Received on 24.02.2011       Modified on 18.04.2011

Accepted on 11.05.2011      © RJPT All right reserved

Research J. Pharm. and Tech. 4(8): August 2011; Page 1197-1200